The goal of the current proposal is to develop a brain penetrating erythropoietin (EPO) analogue with negligible hematopoietic side effects, for AD. EPO is a unique therapeutic candidate for AD since it targets a spectrum of process that are involved in the pathophysiology and disease progression of AD, and importantly, promotes neurogenesis and improves cognition. This is clearly distinct from the numerous anti-A? agents that are currently under development for AD since anti-A? agents do not reverse the existing neuronal damage or cognitive decline. EPO on the other hand has both neuroprotective and neuroregenerative properties. This provides the scientific rationale to develop EPO for AD. Two major obstacles to the development of EPO for AD are: a) limited blood-brain barrier (BBB) penetration necessitating transcranial administration or use of high doses, and b) high doses of EPO result in undesired hematopoietic effects. To achieve our goal, a fusion protein of EPO with a monoclonal antibody (MAb) against the mouse transferrin receptor (TfR) has been engineered and is designated as cTfRMAb-EPO. The cTfRMAb-EPO fusion protein offers dual advantages: a) it rapidly enters the brain via the BBB TfR and b) it is rapidly cleared from the systemic circulation via the peripheral TfR, resulting in negligible hematopoietic effects. Our central hypothesis is that chronic systemic administration of the cTfRMAb-EPO fusion protein modifies multiple targets of AD pathophysiology and disease progression (A?-pathology (?), neuroinflammation (?), synaptic loss (?), neurogenesis (?), cognitive function (?), and is thus therapeutic in AD with negligible hematopoietic effects. In the proposed studies, APPswe, PSEN1dE9 (APP/PS1) mice will be treated with either the cTfRMAb-EPO fusion protein, recombinant human EPO (rhuEPO) or vehicle, and the following specific aims will be addressed: Aim 1: Determine the cytoprotective effects of the cTfRMAb-EPO fusion protein in the APP/PS1 mice. Specifically, microglial activation (CD11b), neuroinflammation (brain cytokine levels), neurodegeneration (FluoroJade C), synaptic loss (synaptophysin) and neurogenesis (5-bromo-2?-deoxyuridine immunostaining) will be studied. Additionally, we will also study the effect of the brain-penetrating EPO on hematocrit, serum chemistry and histological effects on major organs following chronic dosing; Aim 2: Characterize the effects of the cTfRMAb-EPO fusion protein on cognitive deficits in the APP/PS1 mice. In particular, recognition memory and exploration will be assessed using the novel object recognition and open-field activity tests; Aim 3: Determine the effects of the cTfRMAb-EPO fusion protein on A?-pathology in the APP/PS1 mice. Specifically, the effect of the cTfRMAb- EPO fusion protein on A? plaque burden will be studied. The proposal will underscore the need for a neuroprotective-neuroregenerative approach for AD and provide a drug-delivery strategy to deliver EPO to the brain with negligible hematopoietic side effects.